Dihydromyricetin alleviates immunosenescence by modulating the TAK1/MAP3K7 Axis

Aging is frequently associated with a progressive loss of physiological integrity, with immunosenescence and chronic inflammation playing pivotal roles in this process. While natural compounds like Dihydromyricetin (DHM) exhibit significant anti-aging potential, its precise upstream immunomodulatory targets and cross-species conservation remain largely elusive. Through a combination of transcriptomic analyses and cross-species assays, we demonstrated that DHM systematically downregulates basal antimicrobial peptide expression to resolve chronic inflammaging in Drosophila, while simultaneously maintaining robust acute pathogen clearance. Furthermore, DHM significantly suppressed the senescence-associated secretory phenotype (SASP) in a mammalian H₂O₂-induced stress-induced premature senescence (SIPS) model. Crucially, genetic silencing revealed that the immune-regulatory kinase TAK1 (and its mammalian homolog MAP3K7) is fundamentally required for the lifespan-extending benefits of DHM in Drosophila and mediates the suppression of key SASP components, such as IL-1β and IL-8, in mammalian fibroblasts. These findings suggest that the TAK1/MAP3K7 axis serves as a crucial conserved node mediating a significant portion of DHM's cross-species anti-aging effects. This study underscores the therapeutic potential of targeting the TAK1 axis with natural compounds to combat age-related immune dysregulation.